tbuckley/cabot-search huggingface dataset:
Platinum-based chemotherapy in patients with castration-resistant prostate cancer and hepatic metastases.
Authors: Gunhild Von Amsberg, Lukas Lunger, Christopher Darr, Nadja Strewinsky, Tobias Busenbender, Moritz Kaune, Pierre Tennstedt, Lisa Steinhelfer, Margitta Retz, Markus Sauer, Amir Karimzadeh, Timo Bartel, Ken Herrmann, Boris A. Hadaschik, Viktor Grünwald, Wolfgang P. Fendler
Journal: Journal of Clinical Oncology (2023)

e17063 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and hepatic metastases face a dismal prognosis. In fact, the majority of phase 3 trials show no benefit of novel treatment modalities including Lutetium PSMA radioligand therapy (LuPSMA-RLT) in comparison with standard therapies for the subgroup of visceral metastases. In aggressive variant prostate cancer, the addition of platinum resulted in a clinically relevant improvement of progression free survival (PFS) and overall survival (OS). Whether adding platinum is also beneficial in unselected mCRPC patients with hepatic metastasis is unclear. Methods: We retrospectively analyzed mCRPC patients diagnosed with hepatic metastasis and treated with platinum-based chemotherapy or LuPSMA-RLT in three German centers (Hamburg, Essen, Munich). Patients with pure neuroendocrine prostate cancer were excluded. Survival rates and 95% confidence intervals (CI) were compared using the Kaplan Meier method and the logRank test. Results: A total of 84 mCRPC patients with hepatic metastasis who had received at least one platinum-based therapy and 32 patients treated with LuPSMA-RLT were evaluated. Median age at treatment initiation was 67 and 73 years. Patients had undergone a median of three treatment lines (83% ≥ 1 new hormonal agent (NHA); 87% ≥ 1 taxane based chemotherapy) before initiation of platinum based chemotherapy and a median of 4 treatment lines before LuPSMA-RLT. Median time to initiation of 1 st platinum-based chemotherapy after diagnosis of liver metastases was 55 days. In total, 37% received carboplatin/cabazitaxel, 26% cisplatin or carboplatin/ etoposide, 11% carboplatin/docetaxel, and 26% other platinum-based combination therapies. In the platinum-treated group, 52.6% and 27% of the patients did not show progression at 3 and 6 months after treatment initiation as compared to 44.1% and 19.3% of the patients who received LuPSMA-RLT with a median PFS of 3.1 and 2.4 months, respectively. At 6 months 71.3% of the platinum-treated patients and 56.6% of the LuPSMA-RLT were alive. Overall, BRCA1/2 status was available for 53 of the platinum-treated patients, 15% of whom had a pathogenic alteration in either gene. This small subgroup was found to have a similar OS compared to the overall cohort. Conclusions: Platinum-based chemotherapy showed promising activity in mCRPC patients with hepatic metastasis. Given the high unmet medical need, platinum-based combination therapies should be further evaluated prospectively. [Table: see text]
Commercial vs. Medicaid insurance and use of high-priced anticancer treatments.
Authors: Aaron Philip Mitchell, Alan C Kinlaw, Sharon Peacock Hinton, Stacie B Dusetzina, Hanna Kelly Sanoff, Jennifer Leigh Lund
Journal: Journal of Clinical Oncology (2023)

6599 Background: Financial incentives presented by the larger markups on cancer drugs among commercial payors may result in increased use of high-priced drugs among commercially insured vs. Medicaid insured patients. We evaluated the association between patient insurance type and the likelihood of receiving higher-priced treatments. Methods: We linked cancer registry, administrative claims, and demographic data for individuals diagnosed with cancer in North Carolina from 2004-2011, who had either commercial or Medicaid insurance. We selected cancer types with multiple FDA-approved, guideline-recommended chemotherapy options, and large differences in price between the higher-priced and lower-priced options during the study period: advanced colorectal, lung, and head-and-neck cancer (HNC). The primary outcome was receipt of the higher-priced treatment option, and the primary exposure was insurance type: commercial vs. Medicaid. We estimated risk ratios (RR) for the association between insurance type and higher-priced treatment using log binomial models with inverse probability of exposure weights to control confounding by age, county-level poverty prevalence, and selected comorbidities. We assessed for potential modification of the RR by setting (hospital outpatient vs. physician office) and academic designation (NCI-designated comprehensive cancer center vs. other); these were exploratory analyses due to sparse data and subsequently limited confounding control. Results: Of 812 patients: 209 (26%) had Medicaid insurance; 311 (38%) had NHC, 263 (32%) colon or rectal cancer, and 238 (29%) lung cancer. The crude risk of higher-priced treatment was 36% (215/603) for commercially insured and 27% (57/209) for Medicaid insured (RR:1.31, 95%CI 1.02-1.67). After weighting the association was attenuated (RR:1.15, 95%CI 0.81-1.65). While limited by imprecision and the potential for uncontrolled confounding, exploratory subgroup analysis suggested that, compared to Medicaid insurance, commercial insurance was associated with numerically higher risk of higher-priced treatment among patients treated by non-NCI designated providers (RR:1.53, 95%CI 1.14-2.04), and within both the physician office (RR:1.36, 95%CI 0.95-1.95) and hospital outpatient (RR:1.08, 95%CI 0.58-2.02) settings, but lower risk of high-priced treatment within NCI cancer centers (RR:0.39, 95%CI 0.22-0.71). Conclusions: Individuals with Medicaid vs. commercial insurance access high-priced treatments at a similar proportion after accounting for differences in case mix, morbidity, and SES. However, modification of the association by and academic setting, observed in exploratory subgroup analysis, suggests the possibility that insurance type may affect treatment for some patient groups. This study was limited by focus on a single state and the potential for residual confounding.
Prognosis stratification by a mutational signature in metastatic prostate cancer.
Authors: Gejun Zhang, Huanhuan Liu, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e17079 Background: Metastatic prostate cancer (mPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis. Classification of patients with similar mutation profiles may help identifying subgroups of patients outcomes. However, classification based on somatic mutations is challenging due to the sparseness and heterogeneity of the data. Methods: A retrospective study was performed to identify the prognosis-related somatic mutations of mPC in 453 MSK-IMPACT, 1945 MSK-MET and 93 The Cancer Genome Atlas (TCGA) database. Cox regression were performed to screen out prognostic genes. Results: In the MSK-IMPAC cohort, a total of 35 genes were related with overall survival (OS). We selected genes mutated in at least 4 patients, leaving 6 genes (APC, ZFHX3, NCOR1, ASXL2, ARID1A, JAK1genes). We then recruited this mutation and formed a total number of 6-gene signature. Compared with the wildtype group, the OS of mutated signature was markedly lower, with p = 0.033. Similarly, the mutated signature harbored a lower OS than that in the wildtype group in the MSK-MET cohort (p = 0.001). In mutated signature cohorts, the five most frequently mutated genes were APC(45%), TP53 (42%), ZFHX3 27%), FOXA1(14%), and PTEN (13%). Dissimilarly, the five most frequently mutated genes were TP53 (43%), FOXA1 (10%), PTEN (9%), SPOP (7%), and CDK12 (7%) in wildtype cohorts. Furthermore, patients with mutated signature had higher WNT pathway (47.5% vs 14.8%), PI3K pathway (38.8% vs 12.0%), and NOTCH pathway (19.42% vs 6.0%) than those in the patients without mutated signature. Conclusions: These data underline the potential value of using somatic mutations to accurately stratify mPC patients into clinically actionable subgroups.
Adenocarcinoma in villous adenoma: Demographics analysis.
Authors: Erin Sinai, Beau Hsia, Madison Cook, Andrew Luker, Xinxin Wu, Peter T. Silberstein, Darby Keirns
Journal: Journal of Clinical Oncology (2023)

e18024 Background: Adenocarcinoma in Villous Adenoma (AVA) is a metastatic disease that arises from villous adenomas. These adenocarcinomas can arise from different tissues, particularly this analysis looked at AVA arising from the head and neck region. Treatment for otolaryngological AVA varied depending on grade, but the majority of patients received surgery or radiation. Despite its rarity, 16.7% of patients pass within 90 days after receiving surgery for this cancer. Given the rarity, data analysis of demographic findings could provide important information regarding its occurrence and distribution in the population. Methods: Patients from the National Cancer Database (NCDB) with a confirmed diagnosis of otolaryngological AVA from 2004–2017 were used in a retrospective cohort analysis (N = 33). Factors analyzed by descriptive statistics and regression analysis include sex, race, average household income, Charlson-Deyo score, palliative care obtained, and year of diagnosis. Results: A total of 33 patients were identified in the database with a confirmed diagnosis of AVA in the head and neck between 2004 – 2017 with a steady incidence of patients diagnosed per year (R2 = 0.0). The average age of diagnosis was 69 years (SD = 9.7, range = 51-85 years). The top primary site was the esophagus (90.9%). Most individuals (60.6%) had Charlson/Deyo comorbidity scores of 0. The majority of the patients were Non-Hispanic and White (97.0%). There was an equal distribution of income earners in the first and second quartile (33.3% and 33.3%) compared to those in the third or fourth quartiles (upper and middle quartiles are defined as over $74,063 and $57,857 to $74,062, respectively). A higher percentage of patients were insured by Medicare (57.0%) or privately insured (36.4%), compared to those who were uninsured. Most patients lived in metropolitan counties with a population greater than 1 million (51.6%). The majority of patients were treated in a comprehensive community cancer program (54.5%). Most patients did not receive palliative care (97.0%) and 16.7% of patients died within 90 days of receiving surgical treatment. Conclusions: With most data showing extensive data analysis on AVA stemming from the colon, this is the only analysis of demographic data from this cancer originating from the head and neck region. From the NCDB data, the majority of patients are non-Hispanic and White with a primary-site diagnosis presenting in the esophagus. This is the first time that specific AVA socio-economic data has been analyzed: patients with this cancer tend to be in upper or middle income brackets, live in crowded metropolitan areas, and have Medicare as their insurance coverage. To further our understanding of otolaryngological AVA, it would be necessary to examine the relationship between demographic and socioeconomic factors, and the diagnosis, treatment options, and survival rates for individuals with AVA.
Development of a plasma biomarker panel for gastric cancer detection based on an autoimmune response signature.
Authors: Rongzhang Dou, Ehsan Irajizad, Yining Cai, Johannes Fahrmann, Jody Vykoukal, Hiroyuki Katayama, Yihui Chen, Ali Hussein Abdel Sater, Melissa Pizzi, Edwin J. Ostrin, Kohei Yamashita, Jaffer A. Ajani, Samir M Hanash
Journal: Journal of Clinical Oncology (2023)

e16101 Background: Gastric cancer is frequently diagnosed at an advanced stage and is associated with poor outcomes. A humoral immune response to tumor antigens in the form of autoantibodies occurs early during tumor development. Harnessing autoantibodies and corresponding antigens has potential for diagnostic and therapeutics applications. Methods: Plasma samples from gastric cancer patients were collected before treatment and from non-gastric cancer cases and healthy controls for identification and quantitative analysis of immunoglobin (Ig)-bound antigens using mass spectrometry. The Ig-bound antigens were pulled down with a Protein A/G column for analysis by mass spectrometry. A protein A/G plate capture enzyme-linked immunosorbent assay (ELISA) was developed to validate Ig-bound MS results. A combined biomarker panel was established based on a logistic-regression model and ROC analysis was used to assess panel performance. Results: From a total of 983 proteins identified from gastric cancer samples, four Ig bound proteins were found to be enriched in gastric cancer plasmas compared with healthy controls and plasmas from other cancer types which yielded an area under the curve (AUC) of 0.973 (95% confidential interval [CI] = 0.92-1.00) for gastric cancer discrimination with a sensitivity of 0.91 at 95% specificity. Enzyme-linked immunosorbent assay (ELISA) based data yielded a high correlation (r = 0.72, P = 0.0199) with Ig-bound mass spectrometry data. These four proteins were found to be highly expressed in gastric cancer based on TCGA transcriptomic data with concordant tumor cell proteomic data. Conclusions: Our data reveal a panel of plasma Ig-bound antigens associated with the development of gastric cancer with potential application for gastric cancer detection and monitoring and potential therapeutic relevance.
Efficacy and safety of perioperative chemotherapy combined with tislelizumab and trastuzumab for HER2-positive resectable gastric/gastroesophageal junction cancer (GC/EGJC): Preliminary results of a phase 2, single-arm trial.
Authors: Chunlin Zhao, Xiangrui Meng, Zhengzheng Shan, Jianwu Jiang, Xinyu Liu, Haohao Li, Junfeng Sun, Chaohui Ding, Jin Xia, Zhiqiang Liu, Feng Wang
Journal: Journal of Clinical Oncology (2023)

e16084 Background: Recently, immunotherapy combined with trastuzumab and chemotherapy have been recommended by the clinical guidelines of many countries as the first-line treatment for advanced HER2-positive G/GEJ adenocarcinoma. Combining chemotherapy with tislelizumab and trastuzumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable HER2-positive GC/GEJC. Methods: This study is a multicenter, single-arm, open-label phase 2 study (NCT04819971). Patients with histologically confirmed cT2-4NxM0 or cTxN+M0, (TNM 8th edition), resectable gastric adenocarcinoma are eligible for this study. Neoadjuvant therapy will be administered for four cycles. The patients will receive tislelizumab and trastuzumab for 1 cycle (Q3W), followed by tislelizumab and trastuzumab combined with DOS (Docetaxel + Oxaliplatin + S-1) for 3 cycles (Q3W). Surgery is planned 4-6 weeks after preoperative treatment. Patients who have complete surgical resection will receive adjuvant therapy starting within 4–6 weeks after surgery for 6 cycles (three cycles of tislelizumab and trastuzumab combined with DOS regimen, followed by 6 weeks of tislelizumab and trastuzumab for 6 cycles. The primary endpoint was pathological complete response rate (pCR). Secondary endpoints included R0 resection rate, 1-year and 2-year event-free survival (EFS), overall survival (OS) and safety. Results: From September 13, 2021 to February 01, 2023, 12 patients were enrolled (58.0% male, median age 61 years old), and the median follow up time was 7.3 months (0.4-16.9). Seven patients completed surgery, and 5 patients were undergoing neoadjuvant therapy. The R0 resection rate was 100%, 3 patients (42.9%) achieved pCR, and 4 patients (57.1%) achieved major pathological remission (MPR). Postoperative pathology showed tumor downstaging in 5 cases after neoadjuvant therapy, with a decrease rate of 71.4%. Median OS and EFS have not been reached. The most common AEs (all grades, grade ≥3) were anemia in 1 (8.3%) and neutropenia in 1 case (8.3%). The immune-related adverse events were all grade 1 included 2 thyroid dysfunction (16.7%), 1 abnormal liver function (8.3%), and 1 of elevated blood sugar (8.3%). No grade 3 or higher immune-related AE was observed. No treatment related deaths were reported. Conclusions: According to the preliminary results, tislelizumab combined with trastuzumab and standard chemotherapy in the perioperative period of HER2-positive GC and EGJ have a good clinical benefit trend and controllable security. Clinical trial information: NCT04819971 .
Personalized therapy for head and neck squamous carcinoma (HNSCC) utilizing tissue proteomics profiling.
Authors: Sheeno P. Thyparambil, Wei-Li Liao, Amanda Strasbaugh, Marya Abebe Melkie, Negin Ghafourian, Robert Heaton, Xuefeng Ling
Journal: Journal of Clinical Oncology (2023)

6045 Background: Chemotherapy is widely used in the treatment of HNSCC, yet no biomarkers for chemotherapy is used for selection of the chemo agent in the treatment of HNSCC. We examined 143 HNSCC cancer using targeted proteomics for the protein expression levels of several chemo agents. These include markers of resistance to platinum agents (ERCC1), anti-tubulin inhibitors (TUBB3) and sensitivity markers for topoisomerase inhibitors (Topo1 – irinotecan, topotecan; Topo2A – doxorubicin, etoposide). We also measured markers for several antibody-drug conjugates (EGFR, Her2, Trop2, FR-alpha, Mesothelin). Methods: Tumor areas from Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from clinical samples of HNSCC that were received at our CLIA certified laboratory were microdissected and a selected reaction monitoring mass spectrometry (SRM-MS) quantitative proteomic analysis of 72 protein biomarkers were conducted concurrently from 2-3 sections of FFPE tissue. Results: Platinum agents are widely agent in HNSCC cancer. ERCC1, a resistance marker for platinum agents was expressed in 44% of HNSCC. Similarly, TUBB3, a resistance marker for Paclitaxel, docetaxel was also expressed in ~45% of HNSCC. These indicate that ~45% of HNSCC could potentially be refractory to platinum and paclitaxel-based therapy. Additionally, ALDH1A1, a marker for resistance of cyclophosphamide, was expressed in 78% of HNSCC. Temozolomide, an alkylating agent used in other cancer type could be beneficial in 14% of HNSCC because of the lack of resistance marker MGMT. On the other hand, 88% of HNSCC expressed Topo1, which is a sensitivity marker for irinotecan or topotecan based therapy. Additionally, Top1 is also the target for the payload of several ADCs (e.g. trastuzumab deruxtecan and sacituzumab govitecan). Similarly, 55% of HNSCC expressed Topo2A, a target for etoposide and doxorubicin. Additionally, 57% of HNSCC expressed hENT1, a transporter of gemcitabine. HNSCC also expressed various targets for targeted and ADC agents. These include EGFR (86% detected with 37x range of distribution), Her3 (11%), IGF1R (16%), MET (13%), Folate receptor- alpha (18%), Mesothelin (13%), and Trop2 (89% with 134x range of distribution). Her2 was overexpressed ( &gt; 750 amol/ug) in 11% of HNSCC, however, it was observed in 46% of HNSCC with a 53x range (276 – 14705 amol/ug), indicating that a significant population of HNSCC might be eligible for low Her2 clinical trials. Conclusions: Every cancer is unique, and the ability to analyze 72 protein biomarkers from 2-3 FFPE sections simultaneously at the same time provides a wealth of actionable information for clinical treatment or patient stratification for clinical trials.
A novel orally bioavailable small molecular ENPP1 inhibitor (OC-1) for cancer immunotherapy.
Authors: Jiyun Chen, Brahmam Pujala, Ashu Gupta, Amantullah Ansaria, Farha Khana, Elbert Lee, Sarvajit Chakravarty
Journal: Journal of Clinical Oncology (2023)

e15136 Background: Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) is a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities. Inhibiting ENPP1 activity has emerged as an attractive approach in cancer immunotherapy, based on two distinct mechanisms. One mechanism is the stabilization of cyclic GMP–AMP (2’3’-cGAMP), which binds to stimulator of IFN genes (STING) and functions as an endogenous second messenger to activate the innate immune system; the other is the lowering of adenosine concentrations in the tumor microenvironment. ENPP1 inhibitors have shown promising monotherapy activity and synergy with various targeted therapies in preclinical models. Methods: OC-1 was characterized, for activity and selectivity, in the following in vitro assays: a luminescence-based enzymatic assay; cell proliferation assays; selectivity assays against 15 phosphodiesterases (PDE) based on inhibition of enzymatic activity; and a cytokine release assay in human THP cells and mouse splenocytes looking at changes in IFN-β/CXCL10. Oral bioavailability of OC-1 in mice and rats was studied following oral gavage. Plasma exposures were quantified using standard LC/MS/MS methods. In vivo tumor growth inhibition (TGI) of OC-1 was evaluated in syngeneic mouse tumor models (CT26 and MC38), as monotherapy and in combination with an anti-PD1 antibody. OC-1 was dosed orally in all in-vivo models. Results: We have discovered a novel small molecule inhibitor of ENPP1, OC-1, with a Ki value less than 10 nM in an ENPP1 enzymatic assay. Increase in gene expression of IFN-β and CXCL10/IP10 was observed in OC-1-treated THP1 cells. No inhibition in cell proliferation in various cancer lines was seen up to the highest concentration tested (30 µM). OC-1 was also selective against 15 PDEs with IC 50 &gt; 30 µM. The mean oral bioavailability of OC-1 was 72% and 63% in mice and rats, respectively. OC-1 showed single agent activity (20 – 40% TGI) and combination activity of approximately 75% TGI when it was combined with an anti-PD-1 antibody in in vivo efficacy studies with no impact on body weight. Conclusions: In summary, OC-1 is an orally bioavailable ENPP1 inhibitor with promising anti-tumor activity in preclinical models. Its physicochemical properties make it a suitable candidate for clinical investigation.